This invention relates to a method for the control of pathogenic fungi and, more particularly, to the selective fungicidal treatment of Cryptococcus neoformans with 4-oxatetradecanoic acid.
Candida albicans, a diploid asexual yeast, and Cryptococcus neoformans, a heterothallic basidomycete, are major causes of systemic fungal infections in patients with acquired immunodeficiency syndrome (AIDS).
Species of the genus Candida are part of the normal human flora and are the most common yeast pathogens. Candida albicans, a dimorphic, asexual yeast, is the most frequently identified pathogen among Candida species. Systemic Candida infections commonly occur in patients who have been immunocompromised by treatment with immunosuppressive medication and broad spectrum antibiotics but are not as frequent in patients with AIDS.
Cryptococcus neoformans is the only encapsulated yeast known to be pathogenic in humans. Unlike C. albicans, C. neoformans is heterothallic, i.e. it has asexual forms with stable mating types. The polysaccharide capsule of C. neoformans has an .alpha.-1,3 mannose backbone with associated glucuronosyl and xylosyl side chains. There are four serotypes of C. neoformans; A, B, C and D, each with differing amounts of xylosyl moieties in their capsules. Two varieties are recognized: C. neoformans var. neoformans (serotypes A and D) and C. neoformans var. gatti (serotypes B and C). The capsule is one of the factors that determines the virulence of C. neoformans. Infection occurs via inhalation of aerolized spores. Depending on the infecting dose and immunologic status of the patient, chronic systemic infection can occur affecting the lung, skin or meninges. In immunocompromised patients, such as those with AIDS, cryptococcosis has a more malignant course, frequently presenting with bizarre cutaneous manifestations and spreading to the central nervous system where it is often refractory to treatment.
At the present time, therapy for systemic C. albicans and C. neoformans infections is less than ideal. Patients are currently treated with amphotericin B alone or in combination with the nucleoside analog 5-fluorocytosine. Alternatively, lanosterol 14.alpha.-demethylase inhibitors such as the imidizaole ketoconazole or the triazole fluconazole are used. Cryptococcosis in AIDS patients, unlike in immunocompetent hosts, is frequently resistant to treatment with amphotericin B and 5-fluorocytosine. Moreover, while amphotericin B is the only fungicidal agent available, it is nephrotoxic, does not penetrate into the cerebrospinal fluid, and must be given intravenously. Ketoconazole and the newer azoles are fungistatic rather than fungicidal. These problems are particularly important in patients with AIDS: 40-50% fail primary therapy and no therapy currently available is curative.
Gershon et al., J. Pharmaceut. Sci. 68, 82-84 (1979), synthesized a series of n-alkoxyacetic acids (ROCH.sub.2 COOH) where n=C1-C9, C11 or C13, and tested their effects on the growth of a variety of fungal species, including C. albicans, in Sabouraud dextrose agar. While 3-oxaundecanoic acid had the broadest spectrum and highest potency, several other compounds, including 3-oxatetradecanoic acid, inhibited growth. The mechanism(s) that are responsible for these anti-fungal effects were not defined.
C.sub.13 -C.sub.14 Fatty acid analogs in which a methylene group normally in carbon position from 4 to 13 is replaced with oxygen are disclosed as useful antiviral agents, e.g. retroviruses such as HIV-1, in U.S. Pat. No. 5,073,571. In particular, 13-oxatetradecanoic acid, which is a substrate for human acyl CoA synthetase and human myristoylCoA:protein N-myristoyltransferase (NMT), inhibits HIV-1 replication in acutely and chronically infected human T-lymphocyte cell lines at doses which do not cause cellular toxicity. See, e.g., Bryant et al., Proc. Natl. Acad. Sci. USA 86, 8655-8659 (1989); Bryant et al., Ibid 88, 2055-2059 (1991); Devadas et al., J. Biol. Chem. 267, 7224-7239 (1992). Studies with tritiated 13-oxatetradecanoic acid indicate that this fatty acid analog is incorporated into HIV-1 Pr55.sup.gag and nef and some but not all cellular proteins. See, Johnson et al., Proc. Natl. Acad. Sci. 87, 8511-8515 (1990); Bryant et al., Ibid. 88, 2055-2059 ( 1991).